Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai East Hospital, Tongji University, School of Medicine, Shanghai, China.
Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Key Laboratory of Diabetes, Department of Endocrinology and Metabolism, Shanghai, China.
Cell Death Dis. 2021 Jul 14;12(7):701. doi: 10.1038/s41419-021-03993-1.
The mitochondrial DNA m.3243A > G mutation is well-known to cause a variety of clinical phenotypes, including diabetes, deafness, and osteoporosis. Here, we report isolation and expansion of urine-derived stem cells (USCs) from patients carrying the m.3243A > G mutation, which demonstrate bimodal heteroplasmy. USCs with high levels of m.3243A > G mutation displayed abnormal mitochondrial morphology and function, as well as elevated ATF5-dependent mitochondrial unfolded protein response (UPR), together with reduced Wnt/β-catenin signaling and osteogenic potentials. Knockdown of ATF5 in mutant USCs suppressed UPR, improved mitochondrial function, restored expression of GSK3B and WNT7B, and rescued osteogenic potentials. These results suggest that ATF5-dependent UPR could be a core disease mechanism underlying mitochondrial dysfunction and osteoporosis related to the m.3243A > G mutation, and therefore could be a novel putative therapeutic target for this genetic disorder.
线粒体 DNA m.3243A>G 突变众所周知可引起多种临床表型，包括糖尿病、耳聋和骨质疏松症。在这里，我们报告了从携带 m.3243A>G 突变的患者中分离和扩增尿源性干细胞（USCs）的情况，这些细胞表现出双峰异质性。具有高水平 m.3243A>G 突变的 USCs 显示出异常的线粒体形态和功能，以及升高的 ATF5 依赖性线粒体未折叠蛋白反应（UPR），同时伴随着 Wnt/β-catenin 信号通路和成骨潜能的降低。在突变 USCs 中敲低 ATF5 可抑制 UPR，改善线粒体功能，恢复 GSK3B 和 WNT7B 的表达，并挽救成骨潜能。这些结果表明，ATF5 依赖性 UPR 可能是与 m.3243A>G 突变相关的线粒体功能障碍和骨质疏松症的核心疾病机制，因此可能是这种遗传疾病的一种新的潜在治疗靶点。
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